Dual sigma-1 receptor antagonists and hydrogen sulfide-releasing compounds for pain treatment: design, synthesis and pharmacological evaluation Dichiara, Maria Artacho Cordón, Antonia Turnaturi, Rita Santos Caballero, Miriam González Cano, Rafael Pasquinucci, Lorella Barbaraci, Carla Rodríguez Gómez, Isabel María Gómez Guzmán, Manuel Marrazzo, Agostino Cobos del Moral, Enrique José Amata, Emanuele The development of σ1 receptor antagonists hybridized with a H2S-donor is here reported. We aimed to obtain improved analgesic effects when compared to σ1 receptor antagonists or H2S-donors alone. In an in vivo model of sensory hypersensitivity, thioamide 1a induced analgesia which was synergistically enhanced when associated with the σ1 receptor antagonist BD-1063. The selective σ1 receptor agonist PRE-084 completely reversed this effect. Four thioamide H2S-σ1 receptor hybrids (5a8a) and their amide derivatives (5b8b) were synthesized. Compound 7a (AD164) robustly released H2S and showed selectivity for σ1 receptor over σ2 and opioid receptors. This compound induced marked analgesia that was reversed by PRE-084. The amide analogue 7b (AD163) showed only minimal analgesia. Further studies showed that 7a exhibited negligible acute toxicity, together with a favorable pharmacokinetic profile. To the best of our knowledge, compound 7a is the first dual-acting ligand with simultaneous H2S-release and σ1 antagonistic activities. 2022-06-14T09:13:27Z 2022-06-14T09:13:27Z 2022-02-15 journal article Eur J Med Chem. 2022 Feb 15;230:114091 http://hdl.handle.net/10481/75477 10.1016/j.ejmech.2021.114091 eng http://creativecommons.org/licenses/by-nc-nd/3.0/es/ open access Atribución-NoComercial-SinDerivadas 3.0 España